Summary for 9LHF
| Entry DOI | 10.2210/pdb9lhf/pdb |
| Related | 4YQU |
| Descriptor | Glutathione S-transferase omega-1, 1-[(2~{R})-2-[5-[4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl]pyrrolidin-1-yl]propan-1-one (3 entities in total) |
| Functional Keywords | inhibitor, complex, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 56213.69 |
| Authors | |
| Primary citation | Sun, Y.,Zhang, F.,Zhou, L.,Feng, Y.,Yang, S.,Lu, Q.,Yuan, X.,Hou, W.,Liu, B.,Guo, Z.,Chen, L.,Peng, B.,Yin, X.,Zhang, Y.,Yang, J.,Chen, N.,Lu, W. Discovery of Potent, Allosteric GSTO1 Covalent Inhibitors with a New Binding Mode. J.Med.Chem., 68:24075-24093, 2025 Cited by PubMed Abstract: GSTO1 activates the NLRP3 inflammasome by deglutathionylating NEK7 at Cys253, driving proinflammatory responses. Using PRM-based targeted mass spectrometry, we identified compound as a covalent GSTO1 inhibitor modifying Cys32. Ligand-based optimization generated analogues with diverse activities; among them, exhibited moderate target engagement (/ = 226 M·s), excellent cysteine selectivity confirmed by desthiobiotin iodoacetamide (DBIA)- and alkyne-based ABPP, and superior metabolic stability in human liver microsomes. High-resolution crystal structures revealed an unexpected binding mode occupying a new hydrophobic pocket distinct from known GSTO1 inhibitors. Functionally, covalent targeting of GSTO1-C32 by markedly reduced LPS-induced IL-1β and IL-18 secretion in human monocyte-derived macrophages. Collectively, these results identify as a potent, selective, and metabolically stable lead compound for developing next-generation GSTO1 inhibitors targeting inflammatory diseases. PubMed: 41233953DOI: 10.1021/acs.jmedchem.5c01724 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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